EP0546013B1 - Analogues de glucagon avec des remplacements ou des deletions d'asp-9 - Google Patents

Analogues de glucagon avec des remplacements ou des deletions d'asp-9 Download PDF

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Publication number
EP0546013B1
EP0546013B1 EP91915449A EP91915449A EP0546013B1 EP 0546013 B1 EP0546013 B1 EP 0546013B1 EP 91915449 A EP91915449 A EP 91915449A EP 91915449 A EP91915449 A EP 91915449A EP 0546013 B1 EP0546013 B1 EP 0546013B1
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EP
European Patent Office
Prior art keywords
glucagon
des
pharmaceutically acceptable
addition salt
acid addition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
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EP91915449A
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German (de)
English (en)
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EP0546013A1 (fr
EP0546013A4 (en
Inventor
Robert Bruce Merrifield
Cecilia G. Unson
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Rockefeller University
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Rockefeller University
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Glucagon is a 29-residue peptide hormone that regulates glycogenolysis and glucogenesis.
  • the structure of glucagon may be represented as follows:
  • Insulin as is known, rapidly decreases elevated blood sugar.
  • diabetes is only observed when insulin levels are low and glucagon levels are simultaneously elevated.
  • the absence of insulin allows blood glucose to rise particularly after a meal, and the presence of glucagon causes a further rise in blood glucose.
  • Large amounts of insulin are required to reduce the glucose levels to normal.
  • the maintenance of stable levels is difficult and subject to considerable fluctuation. This wide fluctuation is responsible, at least in part, for the clinical difficulties experienced in diabetes.
  • Glucagon appears to act by binding to liver membrane receptors thereby activating adenylate cyclase which, in turn, triggers a series of reactions including the production of cyclic adenosine monophosphate (cAMP), which activates phosphorylase and inhibits glycogen synthetase, thereby contributing to elevated glucose levels in the blood.
  • cAMP cyclic adenosine monophosphate
  • glucagon antagonists that will bind to the liver membrane but do not have the ability to transduce the signal to activate adenylate cyclase.
  • One such product is N ⁇ - trinitrophenyl [12-homoarginine] glucagon. This product does bind to the glucagon receptor without significant activation of adenylate cyclase. Unfortunately it activates another binding system in the hepatocyte membrane leading to the production of inositol trisphosphate and calcium ions.
  • a useful antagonist will block the action of endogenous glucagon by preventing it from binding to the liver membrane receptors and thereby producing cAMP and glucose in the cell, and the ultimate elevation of blood sugar. Such products would be useful to reduce a diabetic's need for injections or infusion of insulin.
  • glucagon antagonist would (1) be completely inactive toward stimulation of adenylate cyclase and production of cAMP, (2) bind as well as glucagon itself to the liver membrane, (3) compete with glucagon for binding to the membrane, (4) at moderate concentrations fully inhibit the action of glucagon toward the activation of adenylate cyclase; and (5) have a satisfactory inhibition index.
  • the inhibition index is the molar ratio of antagonist to agonist which reduces the biological response to one half of the value for the agonist in the absence of antagonist. It will be discussed more fully hereinafter.
  • a class of glucagon antagonists has now been discovered which substantially fulfills the above criteria and does so with minimum side effects.
  • the class is characterized by the deletion or replacement of the L-aspartic acid residue at the 9-position with an amino acid residue other than an L-dibasic amino acid containing up to 5 carbon atoms, or L-proline.
  • the compounds of this invention are analogs of glucagon or derivatives thereof, such as amides characterized by the removal of the 9-aspartic acid residue or its replacement with an amino acid residue other than an L-dibasic amino acid containing up to 5 carbon atoms, or L-proline.
  • the replacement acid residue for the 9-aspartic acid moiety can be selected from amongst any of the L- and D-form amino acids, both naturally occurring and synethetic, including hydrophobic and hydrophilic amino acids, aliphatic amino acids, aryl amino acids, basic amino acids and acidic amino acids, containing more than 5 carbon atoms.
  • One or more of the other amino acid residues in the glucagon chain may be removed or replaced, but the key to optimum utility appears to be removal or replacement of the 9-aspartic acid residue.
  • Compounds within the scope of the invention also include those from which the histidine residue at the one position, i.e. the amino terminal has been removed. Typical of such compounds are:
  • compounds such as the above, including the amides, from which the amino terminal histidine has been removed comprise the preferred compounds of this invention because they presently appear to have the best therapeutic properties.
  • the products of this invention were synthesized by known solid phase techniques. See, for example, Barany and Merrifield (1979) in The Peptides , eds. Gross and Meienhofer (Academic Press, New York) Vol. 2A, pages 1 to 284.
  • the products can be prepared by manual methods or, for example, on a peptide synthesizer such as the Applied Biosystems 430 unit.
  • Double couplings with preformed symmetric anhydrides in dimethylformamide were used routinely for all tert-butyloxycarbonyl-protected amino acids except for tosyl arginine, glutamine, and asparagine, where N-hydroxybenzo triazole esters in dimethylformamide were required [Konig, W. & Geiger, R. Chem. Ber. 103 , 788 (1970)].
  • the assembled protected peptide-resins were cleaved by the "low/high HF" technique [Tam, J.P., Heath, W.F. & Merrifield, R.B. J. Am. Chem. Soc. 105 , 6442 (1983)], which was developed to avoid a number of potential side reactions.
  • 125 I-labeled glucagon from New England Nuclear was used without further purification for periods up to 1 month after its preparation. Creatine phosphate, creatine kinase, bovine serum albumin, dithiothreitol, GTP, and ATP were from Sigma. A cAMP assay kit containing [8- 3 H]cAMP was from Amersham. Nuflow membrane filters (0.45 um) were from Oxoid (Basingstoke, England).
  • Adenylate Cyclase Assay The assay on liver membranes was performed according to Salomon et al. [Salomon, Y., Londos, C. & Rodbell, M. Anal. Biochem. 58, 541, 548 (1974)]. The released cAMP was mixed with [8- 3 H]cAMP measured with a high affinity cAMP binding protein.
  • the purpose of the membrane binding assay is to measure the ability of analogs of glucagon to bind to liver membrane protein compared to that of glucagon.
  • glucagon analogs of this invention were assayed, they were assayed as amides with natural glucagon amide as a standard, thus eliminating the possibility of imprecision due to the heterogeneity of membrane preparations.
  • C-terminal amides are more active than the corresponding carboxyl compounds. Accordingly, C-terminal amides of the glucon analogs of the invention are the presently preferred compounds of the invention.
  • the relative binding affinity of a given analog is expressed as: (half maximal displacement concentration of glucagon) (half maximal displacement concentration of analog) X 100
  • the purpose of the adenylate cyclase assay is to measure the ability of the compound under test to stimulate the activity of adenylate cyclase.
  • the assays are used to measure relative potency, maximum activity and inhibition index.
  • the inhibition index defined above, was determined from adenylate cyclase assays by two different protocols.
  • the compounds of this invention have an inhibition index up to about 150, but preferably up to about 10, coupled with a membrane binding activity of at least 10%. It is much preferred that the inhibition index be 12 or less, and that the relative binding affinity be at least 10%.
  • the pA 2 value is at least 5 and preferably above 7.
  • the pA 2 value is the negative logarithm of the concentration of antagonist that reduces the response to 1 unit of agonist to the response obtained from 0.5 unit of agonist.
  • the glucagon analogs of this invention also include derivatives having the defined properties. As indicated above, C-terminal amides are actually preferred over the C-terminal carboxyl comopunds. Side chain amides such as amides of dibasic acids are also useful. Esters, especially those based on alkyl or aralkyl alcohols corresponding to the amides may also be employed. Ethers, especially lower alkyl ethers of analogs including Ser, Thr and Tyr amino acid residues are also useful, as are esters of these analogs based on alkyl, aryl and aralkyl acids. Glucagon analogs containing amino acid residues with additional functional group may also be converted to derivatives within the scope of the inveniton. These might inlcude, for example N-acetyl derivatives of diamino acids such as lysine.
  • One class of useful derivatives is based on des-His 1 glucagon analogs in which the hydroxyl group of the amino terminal serine residue has been converted to a 2, 4 - difluorobenzoyl ester.
  • Other hydroxyl and amine substituted amino acids derivatized with 2, 4-difluorobenzoic acid are within the scope of the invention whether or not the histadyl residue at the 1-position is in place.
  • compounds within the scope of the invention may be synthesized and thereafter utilized with one or more of the blocking groups still in place.
  • the products of this invention will generally be administered in the same manner as insulin, i.e. parenterally or by infusion. Since their chemical structure and activity is quite similar to insulin they will generally be administered with the same types of pharmaceutically acceptable excipients as insulin. They may in fact be coadministered with insulin in the same dosage units. They may also be administered simultaneously with the insulin although not in the same composition.
  • the products of the invention are amphoteric they may be utilized as free bases, as acid addition salts or as metal salts.
  • the salts must, of course, be pharmaceutically acceptable, and these will include metal salts particularly alkali and alkaline earth metal salts, suitably potassium or sodium salts.
  • a wide variety of pharmaceutically acceptable acid addition salts are available. These include those prepared from both organic and inorganic acids, preferably mineral acids. Typical acids which may be mentioned by way of example include citric, succinic, lactic, hydrochloric and hydrobromic acids. Such products are readily prepared by procedures well known to those skilled in the art.
  • compositions for injection or infusion can, for example be suspended in an inert oil, suitably a vegetable oil such as sesame, peanut, or olive oil. Alternatively they can be suspended in an aqueous isotonic buffer solution at a pH of about 5.6 to 7.4.
  • useful buffers include sodium citrate-citric acid and sodium phosphate-phosphoric acid.
  • the desired isotonicity may be accomplished using sodium chloride or other pharmaceutically acceptable agents such as dextrose, boric acid, sodium tartrate, propylene glycol or other inorganic or organic solutes.
  • Sodium chloride is preferred particularly when the buffer contains sodium ions.
  • the solutions may be thickened with a thickening agent such as methyl cellulose.
  • a thickening agent such as methyl cellulose.
  • They may be prepared in emulsified form, either water in oil or oil in water. Any of a wide variety of pharmaceutically acceptable emulsifying agents may be employed including, for example acacia powder, or an alkaryl polyether alcohol sulfate or sulfonate such as a Triton.
  • compositions of the invention are prepared by mixing the ingredients following generally accepted procedures.
  • the selected components may be simply mixed in a blender or other standard device to produce a concentrated mixture which may then be adjusted to the final concentration and viscosity by the addition of water or thickening agent and possibly a buffer to control pH or an additional solute to control tonicity.
  • compositions will be provided in dosage unit form containing an amount of glucagon analog which will be effective in one or multiple doses to control glucogenesis or blood sugar at the selected level, normally in the presence of insulin.
  • an effective amount of the therapeutic agent will vary with many factors including the age and weight of the patient, the amount of insulin which is concurrently employed, the blood sugar level to be obtained, the inhibition index of the selected analog, and other factors.
  • Typical dosage units will contain from 0.2 to 0.8 ⁇ g/ml although wide variations from this range are possible while yet achieving useful results.

Claims (10)

  1. Analogue de glucagon caractérisé par l'élimination du résidu d'acide L-aspartique dans la position 9 ou son remplacement par un résidu d'acide animé autre que l'acide aminé L-dibasique comportant jusqu'à 5 atomes de carbone, ou de L-proline et par l'activité de liaison relative d'au moins environ 10 % et un indice d'inhibition allant jusqu'à 150 environ, ou un sel d'addition acide pharmaceutiquement acceptable de ceux-ci.
  2. Analogue de glucagon des - His1 selon la revendication 1, ou un sel d'addition acide pharmaceutiquement acceptable de celui-ci.
  3. Analogue de glucagon des - His1 - [Gly9] selon la revendication 1, ou un sel d'addition acide pharmaceutiquement acceptable de celui-ci.
  4. Analogue de glucagon des - His1 - [Nle9] selon la revendication 1, ou un sel d'addition acide pharmaceutiquement acceptable de celui-ci.
  5. Analogue de glucagon des - His1 - [Lys9] selon la revendication 1, ou un sel d'addition acide pharmaceutiquement acceptable de celui-ci.
  6. Amide de glucagon des - His1 - [Gly9],
    amide de glucagon des - His1 - [Nle9], ou
    amide de glucagon des - His1 - [Lys9],
  7. Composition parentérale pour la maîtrise de la glucogenèse dans les humains, contenant un support pharmaceutiquement acceptable et une quantité pharmaceutiquement acceptable d'un analogue de glucagon, caractérisée par l'élimination du résidu acide L-aspartique dans la position 9 ou son remplacement par un résidu d'acide aminé autre que l'acide aminé L-dibasique contenant jusqu'à 5 atomes de carbone, ou de L-proline et par une activité de liaison relative d'au moins environ 10 % et un indice d'inhibition allant jusqu'à environ 150 ou un sel d'addition acide pharmaceutiquement acceptable de ceux-ci.
  8. Composition parentérale selon la revendication 7, dans laquelle l'analogue de glucagon est un glucagon des - His1, par exemple un glucagon des - His1 - [Gly9], un glucagon des - His1 - [Nle9], ou un glucagon des - His1 - [Lys9], ou un sel d'addition acide pharmaceutiquement acceptable de ceux-ci.
  9. Composition parentérale selon la revendication 7 en forme d'unité de dosage contenant environ 0,2 à 0,8 µg/ml de l'analogue de glucagon.
  10. Composition parentérale en forme d'unité de dosage selon la revendication 9, dans laquelle l'analogue de glucagon est un glucagon des - His1, par exemple un glucagon des His1 - [Gly9], un glucagon des - His1 - [Nle9], ou un glucagon des - His1 - [Lys9], ou un sel d'addition acide pharmaceutiquement acceptable de ceux-ci.
EP91915449A 1990-08-31 1991-08-08 Analogues de glucagon avec des remplacements ou des deletions d'asp-9 Expired - Lifetime EP0546013B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US57597090A 1990-08-31 1990-08-31
US575970 1990-08-31
PCT/US1991/005643 WO1992004042A1 (fr) 1990-08-31 1991-08-08 Analogues de glucagon avec des remplacements ou des deletions d'asp?9¿

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EP0546013A1 EP0546013A1 (fr) 1993-06-16
EP0546013A4 EP0546013A4 (en) 1993-09-15
EP0546013B1 true EP0546013B1 (fr) 1997-12-17

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AT (1) ATE161184T1 (fr)
AU (1) AU8497391A (fr)
DE (1) DE69128479T2 (fr)
WO (1) WO1992004042A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5480867A (en) * 1993-12-29 1996-01-02 The Rockefeller University Glucagon analogs with serine replacements
WO2013004983A1 (fr) 2011-07-04 2013-01-10 Imperial Innovations Limited Nouveaux composés et leurs effets sur le comportement alimentaire

Family Cites Families (2)

* Cited by examiner, † Cited by third party
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US4879273A (en) * 1987-05-22 1989-11-07 The Rockefeller University Glucagon homologs and therapeutic use thereof
JPH06504913A (ja) * 1991-01-17 1994-06-09 ザイモジェネティクス，インコーポレイティド グルカゴンアンタゴニストの検出方法

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ATE161184T1 (de) 1998-01-15
DE69128479T2 (de) 1998-06-04
WO1992004042A1 (fr) 1992-03-19
DE69128479D1 (de) 1998-01-29
EP0546013A1 (fr) 1993-06-16
AU8497391A (en) 1992-03-30
EP0546013A4 (en) 1993-09-15

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